title: Enhanced efficacy of enzyme replacement therapy in Pompe disease through mannose-6-phosphate receptor expression in skeletal muscle.
abstract: Enzyme replacement therapy (ERT) with acid α-glucosidase has become available for Pompe disease; however, the response of skeletal muscle, as opposed to the heart, has been attenuated. The poor response of skeletal muscle has been attributed to the low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle compared to heart. To further understand the role of CI-MPR in Pompe disease, muscle-specific CI-MPR conditional knockout (KO) mice were crossed with GAA-KO (Pompe disease) mice. We evaluated the impact of CI-MPR-mediated uptake of GAA by evaluating ERT in CI-MPR-KO/GAA-KO (double KO) mice. The essential role of CI-MPR was emphasized by the lack of efficacy of ERT as demonstrated by markedly reduced biochemical correction of GAA deficiency and of glycogen accumulations in double KO mice, in comparison with the administration of the same therapeutic doses in GAA-KO mice. Clenbuterol, a selective β(2)-agonist, enhanced the CI-MPR expression in skeletal tissue and also increased efficacy from GAA therapy, thereby confirming the key role of CI-MPR with regard to enzyme replacement therapy in Pompe disease. Biochemical correction improved in both muscle and non-muscle tissues, indicating that therapy could be similarly enhanced in other lysosomal storage disorders. In summary, enhanced CI-MPR expression might improve the efficacy of enzyme replacement therapy in Pompe disease through enhancing receptor-mediated uptake of GAA.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA. dwight.koeberl@duke.edu
authors.forename: Dwight D
authors.initials: DD
authors.lastname: Koeberl
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Luo
authors.forename: Baodong
authors.initials: B
authors.lastname: Sun
authors.forename: Alison
authors.initials: A
authors.lastname: McVie-Wylie
authors.forename: Jian
authors.initials: J
authors.lastname: Dai
authors.forename: Songtao
authors.initials: S
authors.lastname: Li
authors.forename: Suhrad G
authors.initials: SG
authors.lastname: Banugaria
authors.forename: Y-T
authors.initials: YT
authors.lastname: Chen
authors.forename: Deeksha S
authors.initials: DS
authors.lastname: Bali
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002976:Clenbuterol / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D056947:Enzyme Replacement Therapy; D006003:Glycogen / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000201:enzymology* / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D018482:Muscle, Skeletal / Q000201:enzymology*; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism*; D000520:alpha-Glucosidases / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D017527:Receptor, IGF Type 2; D006003:Glycogen; D000520:alpha-Glucosidases; D002976:Clenbuterol